Acetylcholine

1.  Type

Methacholine (provocholine)

1.  Type

2.  Nicotinic or Muscarinic

3.  Effects

1.  choline esters - cholinomimetic drug (additional methyl group added to second carbon of ACh molecule)

2.  Effective on muscarinic receptors but not nicotinic receptors. 

3.  hypotension, lacrimation, salivation, bronchial secretions, sweating, GI and bladder motility, spasm of accommodation

Note:  It is partially refractory to breakdown by AChase and thus has a longer duration of action

Carbachol (Isopto Carbachol)

1.  Type

2.  Muscarinic or Nicotinic

3.  Uses

1.  Choline esters - cholinimimetic drug (NH2 group on the terminal end of the ACh)

2.  potent nicotinic stimulating effects with very little muscarinic effects

3.  used topically on the eye to produce miosis in the treatment of glaucoma. 

Note:  very refractory to inactivation by AChase.  It also releases ACh from cholinergic nerve endings.

Bethanechol (Urecholine)

1.  Type

2.  Structure

3.  muscarinic or nicotinic

4.  Uses

1.  choline esters - cholinimimetic drug

2.  It has both the methyl and NH2 substitutions as seen in both methacholine and carbachol. 

3.  muscarinic

4.  useful in treating post-operative urinary retention and atony of the GI tract.  Also used to treat esophageal reflux due to its stimulatory action on the lower esophageal sphincter.

Note;  is refractory to AChase inactivation

Nicotine

1.  Type

2.  Effects

1.  naturally occurring cholinergic stimulants (alkaloids)

2.  activation of all autonomic ganglia including adrenal medulla and stimulation of the skeletal muscle endplate nicotinic receptors.  When given in high doses, it causes blockade of nicotinic receptors due to sustained depolarization.

Muscarine

1.  Type

2.  Effects

1.  Naturally occuring cholinergic stimulants (alkaloids)

2.  With stimulate all muscarinic receptors whether innervated or noninnervated.  This could cause mushroom poisoning since it comes from a mushroom.

Pilocarpine (isopto Carpine)

1.  type

2.  Muscarinic or nicotinic

3.  Uses

1.  Naturally occurring cholinergic stimulants (alkaloids)

2.  Muscarinic

3.  used in treating glaucoma.  outflow of aqueous humor from the eye is enhanced due to constriction of the iris sphincter muscle and the ciliary body behind the iris.

Physostigmine (generic)

1.  type

2.  Where does it bind?

3.  Can it enter the CNS?

4.  Uses

1.  reversible anticholinesterase agents (increase choliergic function)

2.  binds on the anionic and esteratic sites on the enzyme

3.  it is not highly charged to it can readily enter the CNS.

4.  Treats glaucoma and also atropine poisoning

Neostigmine (prostigmin)

1.  Type

2.  Does it enter the CNS?

3.  Uses

4.  Side effects

1.  reversible anticholinesterase agent (increase cholinergic function)

2.  It does not enter the CNS because it is a quaternary amine.  This is why it doesn't treat atropine intoxication very much.

3.  Used in treatment of myasthenia gravis because it directly stimulates nicotinic sites on skeletal muscle endplates.  It is also used to treat curare poisoning along with atropine. 

4.  excessive muscarinic activation (sweating, salivation, increased GI and bladder motility)

Edrophonium (tensilon)

1.  type

2.  Where does it bind?

3.  Uses

4.  Side effects

1.  reversible anticholinesterase agent (increase cholinergic function)

2.  It binds tightly to the anionic site of the enzyme

3.  Administration inhibits AChase only for minutes and thus is valuable for the diagnosis of myasthenia gravis

4.  skeletal muscle weakness (due to either too much AChase inhibition [cholinergic crisis] or insufficient AChase inhibition [myasthenic crisis])

Ambenonium (Mytelase)

1.  Type

2.  Uses

1.  reversible anticholinesterase agents (increase cholinergic function)

2.  treatment for myasthenia gravis

This is a potent reversible anti-AChase compound.

pyridostigmine (mestinon; regonol)

1.  Type

2.  Uses

1.  reversible anticholinesterase agents (increase cholinergic function)

2.  Used in treatment of myasthenia gravis.  This is a potent reversible anti-AChase compound.

donepezil (aricept) and tacrine (cognex)

1.  type

2.  Uses

1.  reversible anticholinesterase agent (increase cholinergic function)

2.  treat cognitive dysfunction seen in patients with Alzheimer's disease

echothiophate (phospholine)

1.  type

2.  Method of action

3.  Uses

1.  irreversible anticholinesterase agent (increase cholinergic function)

2.  this phosphrylates the esteratic site on the AChase enzyme.  It can take weeks and months to regenerate acetylcholinesterase at synaptic junctions.

3.  Used to treat glaucoma, but most are insecticides or potent war gases.  Therefore, you should be concerned with toxicology with irreversible agents.  long term use is restricted to aphakic eyes (lens previously removed for cataracts). 

parathion and malathion

1.  type

2.  Uses

1.  irreversible anticholinesterase agent (increase cholinergic function)

2.  Common insecticides used in agriculture. 

Note:  Parathion is not an antiAChase compound until it is converted by the liver to the active agent paraoxon.  Malathion is quickly inactivated to non-toxic metabolites in mammals and birds.

sarin and soman

1.  type

2.  Uses

1.  irreversible anticholinesterase agent (increase cholinergic function)

2.  these are potent anti-cholinesterase war gases.  Their actions are not reversed by the enzyme reactivators.

pralidoxime (2-PAM)

1.  type

atropine (generic)

1.  type

2.  Method of administration

3. Effect on the CNS

4.  Effects on heart rate

1.  muscarinic blocking drug

2.  Oral

3.  Produces CNS excitation unlike scopolamine.  Confusion, restlessness, excitement, hallucinations, delirium, coma

4.  at low doses we have bradycardia (possibly CNS problem) and at high doses we have tachycardia (peripheral)

scopolamine (generic)

1.  type

2.  Effects on CNS

3.  Uses

1.  muscarinic blocking drug

2.  this has CNS depressant effects unlike atropine.  All of the other effects are like atropine. 

3.  prevent motion sickness by action in the CNS

tropicamide (mydriacyl; others)

1.  type

2.  Characteristics

3.  Uses

1.  muscarinic blocking drug

2.  less potent and much shorter acting muscarinic antagonist. 

3.  more useful for general ophthalmological exams as atropine and scopolamine have prolonged effects.

ipratropium (atrovent) and tiotropium (spiriva)

1.  type

2. Effects in the CNS

3.  Uses

1.  muscarinic blocking drugs

2.  they are quaternary amines and have fewer systemic and CNS side effects

3.  topically applied to airway by means of metered inhaler in patients with COPD because they produce bronchodilation without changing the volume or viscosity of bronchial secretions (as what happens with atropine)

Note:  ipratropium is a second line drug for treatment of bronchial asthma.  tiotropium has a longer duration of action

benztropine (cogentin)

1.  type

2.  Uses

1.  muscarinic blocking drug

2.  CNS acting drug that is used to relieve smptoms of Parkinson's disease

oxybutynin (ditropan)

1.  type

2.  Uses

3.  Method of administration

1.  muscarinic blocking drug

2.  atropine-like agent that is often used to treat spasms of the bladder seen after urologic surgery and in some neurological disorders producing bladder hyperactivity

3.  orally or topically (catheter)

1.  nicotine (ganglionic stimulant)

2.  hexamethonium (ganglionic blockade)

Botulium toxin

1.  method of action

latrotoxin

1.  method of action

Nitric oxide

1.  Where does it come from?

2.  What does it do?

1.  Ach acts on non-innervated muscarinic receptors on endothelial cells of blood vessels and then the endothelial cells release endothelium derived relaxing factor (NO)

2.  causes relaxation of the blood vessel smooth muscle

1.  neuromuscular junction

2.  autonomic ganglia

3.  adrenal medulla (between preganglionic sympathetic splanchnic nerve and chromaffin cells of adrenal gland)

4.  CNS

They complex with enzymes such as acetylcholinesterase and produce an enhancement of cholinergic function.  This cholinomimetic effect will be observed only at those receptors that receive tonic neural input.. you will see muscarinic, nicotinic, and CNS effects (wherever ACh is a NT);  therefore, the non-innervated muscarinic receptors on vascular smooth muscle will not be stimulated. 

They are reversible agents in that the enzymes are eventually freed of the drugs except for there are a few that are so tightly bound that we call them irreversible.

They are used in the treatment of myasthenia gravis and glaucoma.

Physostigimine is useful for treating atropine poisoning.  All compounds are effective as antidotes to curare.

Reversible (6): Physostigmine, Neostigmine, Edrophonium, Ambenoium, Pyridostigmine, Donepezil and Tacrine

Irreversible (3): Echothiophate, Parathion and Malathion, Sarin and Soman

CE reactivator: Pralidoxime (2-PAM)

What are some of the effects of intoxification with anti-AChase agents? 

1.  Muscarinic

2.  Nicotinic

3.  CNS

1.  Muscarinic effects:  bronchoconstriction and bronchial secretions, sweating, salivation, lacrimation, niosis and spasm of accommodation, hypermotility of bladder and GI system, bradycardia

2.  Nicotinic effects:  muscle fasciculations, tachycardia, hypertension (ganglionic stimulation)

3.  restlesness and tremor to convulsions and respiratory and cardiovascular depression

Hexamethonium (C6)

1.  Type

2.  Uses

1.  Ganglionic blocking drug

2.  Only used experimentally because of side effects.  This does not compete with ACh at the nicotinic receptors on the end plate region of the skeletal muscle.